Sudden infant death syndrome (SIDS) remains the leading cause of postnatal infant mortality in the USA. Increasing evidence indicates that SIDS is due to a failure of autoresuscitation, which is a protective brainstem response to asphyxia or severe hypoxia. Gasping is an essential mechanism for autoresuscitation and therefore critically important for survival during severe hypoxia. However, despite considerable relevance, the question how gasping is generated by the nervous system remains largely unknown. We have been able to produce a medullary slice preparation that generates the neuronal correlate for normal breathing and gasping. This slice contains the pre-Botzinger complex (PBC), a region that contains the critical neurons for generating inspiratory activity. During the past funding period we demonstrated that the respiratory network assumes different configurations during normoxia and severe hypoxia: In normoxia the respiratory network is complex and contains cadmium-sensitive (CS) pacemakers, cadmium-insensitive (CI) pacemakers, and three different types of inspiratory nonpacemakers (Nl-3). These neurons are interconnected via excitatory connections that synchronize neuronal activity and facilitate bursting and inhibitory synaptic connections that establish the different phases of respiration and suppress pacemaker activity. In hypoxia, CS pacemakers and the majority of nonpacemakers shut down through the activation of KATP channels. As a consequence inhibitory transmission is greatly diminished, respiratory phases are lost. CI pacemakers and a subpopulation of nonpacemakers are disinhibited and continue to burst throughout hypoxia. CI pacemakers depend on endogenous serotonin receptor 2A activation. Blockade of either CI pacemakers or serotonin receptor 2A activation abolishes gasping indicating that these CI pacemakers become the major drivers of gasping. In the proposed research we aim at examining the modulatory mechanisms that lead to the reconfiguration of the respiratory network. We specifically examine the hypothesis that the transition from normal respiratory activity into gasping is controlled by noradrenergic inputs arriving from pontine A6 and A5 neurons and from medullary A1/C1 neurons. We hypothesize that these noradrenergic neurons not only control pacemaker activity and thereby modulate normal respiration and gasping but also vice versa respiratory pacemakers control activity of these noradrenergic nuclei. Our study will provide mechanistic insight into the neuronal control of attention during normoxia and the control of arousal during hypoxia-induced gasping. Our studies are directly relevant for SIDS as increasing evidence indicates that SIDS victims have diminished gasping and fail to arouse. Moreover SIDS victims have disturbed noradrenergic and serotonergic metabolism.
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